Spatial risk of Haemaphysalis longicornis borne Dabieshan tick virus (DBTV) in China.

The uncertainty and unknowability of emerging infectious diseases have caused many major public health and security incidents in recent years. As a new tick-borne disease, Dabieshan tick virus (DBTV) necessitate systematic epidemiological and spatial distribution analysis. In this study, tick samples from Liaoning Province were collected and used to evaluate distribution of DBTV in ticks. Outbreak points of DBTV and the records of the vector Haemaphysalis longicornis in China were collected and used to establish a prediction model using niche model combined with environmental factors. We found that H. longicornis and DBTV were widely distributed in Liaoning Province. The risk analysis results showed that the DBTV in the eastern provinces of China has a high risk, and the risk is greatly influenced by elevation, land cover, and meteorological factors. The risk geographical area predicted by the model is significantly larger than the detected positive areas, indicating that the etiological survey is seriously insufficient. This study provided molecular and important epidemiological evidence for etiological ecology of DBTV. The predicted high-risk areas indicated the insufficient monitoring and risk evaluation and the necessity of future monitoring and control work.

An Acid-triggered Reactive and Enhanced Fluorescent Probe for Selective Detection of Al3+/H+ and its Application in Real Water Samples and Living Cells.

A reactive fluorescent "turn-on" probe (di-PIP) with imine-linked dual phenanthro[9,10-d]imidazole luminophore have been conveniently prepared as an Al3+ and H+ dual functional receptor. di-PIP displayed high selectivity and sensitivity towards Al3+ ion in DMF/HEPES accompanied by fluorescence blue-shift and a good linear relationship as well as a low detection limit of 30.5 nmol·L-1, which can root from the synergetic functions of the decomposition reaction of di-PIP promoted by acidic Al3+ and the coordination effect between decomposition product and Al3+. Intriguingly, it was found that hydrogen ion H+ can be sufficient for simulating the fluorescence enhancing of di-PIP. 1H NMR titration and MS analyses for elucidation of the intermediate structure further revealed that the acid-triggered decomposition reaction resulted in the rapid, and sensitive sensing to Al3+ and H+. In addition, the probe di-PIP could be successfully applied to the detection of Al3+ in real water samples, and also utilized to visualize Al3+ and H+ in the living cells.

Chloroquine enhances the efficacy of chemotherapy drugs against acute myeloid leukemia by inactivating the autophagy pathway.

Current therapy for acute myeloid leukemia (AML) is largely hindered by the development of drug resistance of commonly used chemotherapy drugs, including cytarabine, daunorubicin, and idarubicin. In this study, we investigated the molecular mechanisms underlying the chemotherapy drug resistance and potential strategy to improve the efficacy of these drugs against AML. By analyzing data from ex vivo drug-response and multi-omics profiling public data for AML, we identified autophagy activation as a potential target in chemotherapy-resistant patients. In THP-1 and MV-4-11 cell lines, knockdown of autophagy-regulated genes ATG5 or MAP1LC3B significantly enhanced AML cell sensitivity to the chemotherapy drugs cytarabine, daunorubicin, and idarubicin. In silico screening, we found that chloroquine phosphate mimicked autophagy inactivation. We showed that chloroquine phosphate dose-dependently down-regulated the autophagy pathway in MV-4-11 cells. Furthermore, chloroquine phosphate exerted a synergistic antitumor effect with the chemotherapy drugs in vitro and in vivo. These results highlight autophagy activation as a drug resistance mechanism and the combination therapy of chloroquine phosphate and chemotherapy drugs can enhance anti-AML efficacy.

Comparison of Surgical or Medical Castration-Related Cardiotoxicity in Patients with Prostate Cancer.

PURPOSE: Androgen deprivation therapy (ADT) includes bilateral orchiectomy or long-acting gonadotropin-releasing hormone (GnRH) agonists/antagonists. It remains controversial with respect to ADT associated cardiovascular outcomes. Hereby, we compared the risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in patients with prostate cancer receiving either surgical castration or GnRH therapies. MATERIALS AND METHODS: Using the Taiwan Cancer Registry and Taiwan's National Health Insurance Research Database, we identified 8,413 patients receiving GnRH therapies compared with 694 receiving surgical castration from 2008 to 2017. The median followup duration was 3 years. RESULTS: The crude incidences of 3-year mortality and MACCEs were 19.90% vs 26.51% and 8.23% vs 8.65% in patients receiving GnRH therapies or surgical castration, respectively. After adjusting for age, cancer stage and comorbidities, despite no significant differences in MACCEs between groups there was a slight increase in the incidence of acute myocardial infarction (AMI) in patients receiving surgical castration compared with those receiving GnRH therapies. The mortality adjusted hazard ratios of MACCEs and AMI among patients receiving surgical castration were 1.11- and 1.8-fold higher than those receiving GnRH therapies. Notably, in subgroup analysis regarding cancer stage, patients with cancer stage IV showed the most significantly increasing risk of AMI in those receiving surgical castration compared with GnRH therapies. CONCLUSIONS: Collectively, we indicated an increased risk of AMI in patients with prostate cancer, especially in patients receiving surgical castration rather than those receiving GnRH therapies. Our findings highlight concerns regarding the cardiac safety of surgical castration compared with GnRH therapies.

Downregulation of c-Myc expression confers sensitivity to CHK1 inhibitors in hematologic malignancies.

Checkpoint kinase 1 inhibitors (CHK1i) have shown impressive single-agent efficacy in treatment of certain tumors, as monotherapy or potentiators of chemotherapy in clinical trials, but the sensitive tumor types and downstream effectors to dictate the therapeutic responses to CHK1i remains unclear. In this study we first analyzed GDSC (Genomics of Drug Sensitivity in Cancer) and DepMap database and disclosed that hematologic malignancies (HMs) were relatively sensitive to CHK1i or CHK1 knockdown. This notion was confirmed by examining PY34, a new and potent in-house selective CHK1i, which exhibited potent anti-HM effect in vitro and in vivo, as single agent. We demonstrated that the downregulation of c-Myc and its signaling pathway was the common transcriptomic profiling response of sensitive HM cell lines to PY34, whereas overexpressing c-Myc could partially rescue the anticancer effect of PY34. Strikingly, we revealed the significant correlations between downregulation of c-Myc and cell sensitivity to PY34 in 17 HM cell lines and 39 patient-derived cell (PDC) samples. Thus, our results demonstrate that HMs are more sensitive to CHK1i than solid tumors, and c-Myc downregulation could represent the CHK1i efficacy in HMs.

Dapagliflozin protects against doxorubicin-induced cardiotoxicity by restoring STAT3.

Doxorubicin (Dox), an effective therapy in different types of cancer, is known to exhibit cardiotoxic effects. Despite previous studies indicating the benefits of dapagliflozin (DAPA) in patients experiencing heart failure, it remains uncertain whether DAPA exerts a protective effect on Dox-induced cardiac dysfunction. Signal transducer and activator of transcription 3 (STAT3) participates in various mechanisms of cardioprotection. Herein, we aimed to investigate the effects of DAPA on Dox-induced cardiotoxicity and the role of STAT3. Sprague-Dawley rats were pretreated with oral DAPA for 6 weeks followed by Dox for 4 weeks. Sequential echocardiography was applied to assess cardiac function. For in vitro analysis, cardiomyocytes were treated with 10 µM DAPA and subsequently exposed to 1 µM Dox. The expression of reactive oxygen species- and apoptosis-related proteins was measured. Using STAT3 siRNA, we further examined the effects of STAT3 effect on DAPA-associated protection against Dox-induced apoptosis. In rats treated with Dox, DAPA significantly reduced cardiac fibrosis and improved cardiac function and hemodynamics. Additionally, DAPA effectively inhibited Dox-induced apoptosis and reactive oxygen species (ROS) in cardiomyocytes. Mechanistically, we showed that DAPA decreased cardiac expression of Bax and cleaved caspase 3 but increased Bcl-2 expression. DAPA also significantly rescued Dox-suppressed STAT3 expression. Conversely, knocking down STAT3 in cardiomyocytes reversed the DAPA-related protective effects on Dox-induced cell apoptosis and ROS. Collectively, our findings indicate that DAPA could be useful for preventing Dox-induced cardiotoxicity by restoring STAT3.

Acute Kidney Injury and Gut Dysbiosis: A Narrative Review Focus on Pathophysiology and Treatment.

Acute kidney injury (AKI) and gut dysbiosis affect each other bidirectionally. AKI induces microbiota alteration in the gastrointestinal (GI) system, while gut dysbiosis also aggravates AKI. The interplay between AKI and gut dysbiosis is not yet well clarified but worthy of further investigation. The current review focuses on the pathophysiology of this bidirectional interplay and AKI treatment in this base. Both macrophages and neutrophils of the innate immunity and the T helper type 17 cell from the adaptive immunity are the critical players of AKI-induced gut dysbiosis. Conversely, dysbiosis-induced overproduction of gut-derived uremic toxins and insufficient generation of short-chain fatty acids are the main factors deteriorating AKI. Many novel treatments are proposed to deter AKI progression by reforming the GI microbiome and breaking this vicious cycle. Data support the benefits of probiotic treatment in AKI patients, while the results of postbiotics are mainly limited to animals. Prebiotics and synbiotics are primarily discussed in chronic kidney disease patients rather than AKI patients. The effect of adsorbent treatment seems promising, but more studies are required before the treatment can be applied to patients. Immune therapy and some repurposed drugs such as allopurinol are prospects of future treatments and are worth more discussion and survey.

Sepsis and Acute Kidney Injury: A Review Focusing on the Bidirectional Interplay.

Although sepsis and acute kidney injury (AKI) have a bidirectional interplay, the pathophysiological mechanisms between AKI and sepsis are not clarified and worthy of a comprehensive and updated review. The primary pathophysiology of sepsis-associated AKI (SA-AKI) includes inflammatory cascade, macrovascular and microvascular dysfunction, cell cycle arrest, and apoptosis. The pathophysiology of sepsis following AKI contains fluid overload, hyperinflammatory state, immunosuppression, and infection associated with kidney replacement therapy and catheter cannulation. The preventive strategies for SA-AKI are non-specific, mainly focusing on infection control and preventing further kidney insults. On the other hand, the preventive strategies for sepsis following AKI might focus on decreasing some metabolites, cytokines, or molecules harmful to our immunity, supplementing vitamin D3 for its immunomodulation effect, and avoiding fluid overload and unnecessary catheter cannulation. To date, several limitations persistently prohibit the understanding of the bidirectional pathophysiologies. Conducting studies, such as the Kidney Precision Medicine Project, to investigate human kidney tissue and establishing parameters or scores better to determine the occurrence timing of sepsis and AKI and the definition of SA-AKI might be the prospects to unveil the mystery and improve the prognoses of AKI patients.

Vancomycin-Associated Acute Kidney Injury: A Narrative Review from Pathophysiology to Clinical Application.

Vancomycin is the most frequently used antibiotic, accounting for up to 35% of hospitalized patients with infection, because of its optimal bactericidal effectiveness and relatively low price. Vancomycin-associated AKI (VA-AKI) is a clinically relevant but not yet clearly understood entity in critically ill patients. The current review comprehensively summarizes the pathophysiological mechanisms of, biomarkers for, preventive strategies for, and some crucial issues with VA-AKI. The pathological manifestations of VA-AKI include acute tubular necrosis, acute tubulointerstitial nephritis (ATIN), and intratubular crystal obstruction. The proposed pathological mechanisms of VA-AKI include oxidative stress and allergic reactions induced by vancomycin and vancomycin-associated tubular casts. Concomitant administration with other nephrotoxic antibiotics, such as piperacillin-tazobactam, high vancomycin doses, and intermittent infusion strategies compared to the continuous infusion are associated with a higher risk of VA-AKI. Several biomarkers could be applied to predict and diagnose VA-AKI. To date, no promising therapy is available. Oral steroids could be considered for patients with ATIN, whereas hemodialysis might be applied to remove vancomycin from the patient. In the future, disclosing more promising biomarkers that could precisely identify populations susceptible to VA-AKI and detect VA-AKI occurrence early on, and developing pharmacological agents that could prevent or treat VA-AKI, are the keys to improve the prognoses of patients with severe infection who probably need vancomycin therapy.

Warm-water footbath improves dysmenorrhoea and heart rate variability in college students: a randomised controlled trial.

The effect of warm-water footbath in improving dysmenorrhoea has been rarely investigated. The study aimed to examine whether a warm-water footbath effectively reduces dysmenorrhoea pain and improves the autonomic nervous system (ANS) activity. The randomised controlled trial was registered at ClinicalTrials.gov. (NCT04071028) We enrolled college students with dysmenorrhoea in Northern Taiwan from December 1 2013 to June 30 2014, and randomised them into footbath (n = 35, median age 19 years) and control groups (n = 33, 18 years). Pain visual analogue scale and Short-Form McGill Pain Questionnaire were used for pain assessment, while heart rate variability (HRV) was measured to assess ANS function. After the interventions, the footbath group significantly improved ANS activity and reduced pain severity comparing to the control group. Furthermore, the changes in HRV positively correlated with the improvement of pain severity. In conclusion, a warm-water footbath is beneficial in improving the pain severity among college students with dysmenorrhoea.Impact StatementWhat is already known on this subject? Dysmenorrhoea is the most common gynaecological condition affecting 34-94% of young women. The existing conventional therapeutic strategies for dysmenorrhoea have potential adverse events. Among the complementary therapies for pain, the warm-water footbath is a widely used thermal therapy in improving peripheral neuropathy symptoms and improving patients' quality of life. The subjects with dysmenorrhoea associate with significantly altered autonomic nervous system (ANS) activity. However, the association among warm-water footbath, menstrual pain and ANS was rarely investigated previously.What the results of this study add? The randomised controlled trial enrolling 68 college students with dysmenorrhoea found warm-water footbath improved ANS activity and reduced pain severity. Furthermore, the changes in heart rate variability positively correlated with pain severity improvement.What the implications are of these findings for clinical practice and/or further research? A warm-water footbath for 20 minutes on menstruation days 1 and 2 is beneficial in improving pain among college students with dysmenorrhoea.